JPH01250386A - Cephalosporin derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is H or the protecting group of the amino group; R<2> is H or the protecting group of the OH; R<3> is H or the protecting group of the carboxyl group; R<4> is H or 1-4C alkyl). EXAMPLE:7beta-{2-(2-Aminothiazol-4-yl)-2-[(Z)-hydroxyimino]acetamide}- 3-[(Z)-2- methoxycarboxylvinylthio]-3-cephem-4-carboxylic acid. USE:The compound exhibits a strong antibiotic power against gram positive bacteria and gram negative bacteria and is useful as an antibiotic for oral administration. PREPARATION:A compound of formula II (R<5> is phenyl, acetyl, etc.), as a starting substance is reacted with NaSH and a compound of formula III. The protecting group of the 7-amino group of the resultant compound is removed and the product is reacted with 2-aminothiazole acetic acid derivative. The obtained compound of formula IV is hydrolyzed and reduced to provide the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to cephalosporin derivatives and non-toxic salts thereof that have excellent antibacterial activity and are useful as pharmaceuticals.

Background of the Invention Cephalosporin derivatives related to the present invention include 2-carboxymethoxyimino-2-(2-carboxymethoxyimino-2-(
Compounds having a 2-aminothiazol-4-yl)acetamide group are known (Japanese Patent Application Laid-Open No. 174086/1986).

- The problem that Ming aims to solve Many cephalosporin antibiotics useful as medicines are known, but most of them have poor oral absorption and are therefore administered parenterally.

The main oral cephalosborin drugs currently used clinically include cephalexin, cefaclor, and cefixime. Inferior to cephalosporin drugs.

Against this background, there is a desire to develop a new oral cephalosvorin agent that has stronger antibacterial activity and a broader antibacterial spectrum.

Means to Solve the Problems As a result of intensive research in order to solve the above problems, the present inventors have developed a drug represented by the following formula l, which has stronger antibacterial activity and a wider antibacterial spectrum than existing oral cephalosborin drugs. The inventors have discovered a novel oral cephalosborin derivative that can be used as a cephalosborin derivative, and have completed the present invention.

The present invention will be explained below.

The present invention is based on the formula (1), (wherein R' represents a hydrogen atom or a protecting group for an amine group,
R1 represents a hydrogen atom or a protecting group for a hydroxyl group, R1 represents a hydrogen atom or a protective group for a carboxyl group, and R4 represents a hydrogen atom and an alkyl group having 1 to 4 R atoms. Phosphorus derivatives and their non-toxic salts.

The functional groups in the present invention each have the following meanings. That is, the amino group-protecting group, the hydroxyl group-protecting group, and the carboxyl group-protecting group refer to protecting groups that are frequently used in the field of β-lactam chemistry. For example, the protecting group for the amino group represented by R' includes a trityl group, a monochloroacetyl group, a formyl group, a benzyloxycarbonyl group, a valanitrobenzyloxycarbonyl group, a valaramethoxybenzyloxycarbonyl group, a t-butoxycarbonyl group, Trimethylsilyl group, etc., and the protecting group for the hydroxyl group represented by R1 includes formyl group, acetyl group, propionyl group, methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, t-butoxycarbonyl group, benzoyl group, toluoyl group, benzenesulfonyl group, tosyl group, phenylacetyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, trityl group,
Such as a tetrahydropyranyl group. Further, the carboxyl group protecting group represented by R8 includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a vinyl group, an allyl group, an ethynyl group,
Methoxymethyl group, ethoxymethyl group, 1-methoxyethyl group, methylthiomethyl group, methylthioethyl group, carboxymethyl group, carboxyethyl group, t-butoxycarbonylmethyl group, 2-(t-butoxycarbonyl)
Ethyl group, benzyl group, varanitrobenzyl group, varamethoxybenzyl group, benzhydryl group, bis-(4-methoxyphenyl)methyl group, 3,4-dimethoxybenzyl group, trityl group, phenethyl group, phenacyl group, 2,
2.2-trichloroethyl group, trimethylsilyl group, 4
-hydroxy-3,5-di(t-butyl)benzyl group,
Phenyl group, tolyl group, xylyl group, etc., and 5-methyl-1,3-dioxacyclobent-4-en-2-one-4-ylmethyl group, which is known in the prodrug formation technology of β-lactam agents. , acetoxymethyl group, pivaloyloxymethyl group, 1-pivaloyloxyethyl group, 1
-acetoxyethyl group, 3-phthalidyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group, 1-(
Impropoxycarbonyloxy)ethyl group, etc.

The alkyl group having 1 to 4 return atoms represented by R4 is
A straight-chain or branched alkyl group, for example,
Examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, and isobutyl group.

On the other hand, the non-toxic salt of the compound represented by formula (■) of the present invention is
means pharmacologically acceptable, such as salts with inorganic bases including sodium, potassium, magnesium, ammonium, etc., salts with organic bases such as triethylamine, cyclohexylamine, basic amino acids such as arginine, lysine, etc. salts with mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid; and salts with organic acids such as acetic acid, lactic acid, tartaric acid, fumaric acid, monoic acid, trifluoroacetic acid, and methanesulfonic acid.

In formula I, preferred examples of R1 and R2 are a hydrogen atom, preferred examples of R3 are a hydrogen atom, or a group known in the art of prodrugging β-lactam agents, such as a pivaloyloxymethyl group, and a group known in the prodrugification technology of β-lactam agents, and a preferred example of R4 is a hydrogen atom or a pivaloyloxymethyl group. Preferred examples include methyl and ethyl groups, respectively.

Furthermore, the compound represented by formula 1 of the present invention has geometric isomers (E-form and 2-isomer, respectively) derived from the oximino group at the 7-position side chain and the vinyl group at the 3-position side chain, and any of them exists. The present invention also includes the following, but the number of geometric isomers derived from the oximino group at the 7-position side chain is preferably two.

The compound represented by the general formula I of the present invention can be obtained, for example, by the production method represented by the following reaction formula [
In the reaction formula, R' and R8 are as defined above except for the hydrogen atom, R1 and R4 are as defined above, and R1 is a phenylacetyl group, phenoxyacetyl group, trityl group, phthaloyl group, It represents a protecting group for an amino group such as a formyl group or a benzoyl group, and R' is a hydrogen atom or a group that can be hydrolyzed in vivo and is known from the prodrug formation technology of β-lactam drugs shown in R' above. and Y is a halogen atom (for example, a chlorine atom, an odor M atom, an iodine atom), a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a diphenylphosphoryloxy group, or a paratoluenesulfonyloxy group. ]
.

or its reactive conductor Step a: First, the compound of the known formula
．． Stir with 0-1.2 molar equivalents. The reaction temperature is -50 to 100°C, preferably -40 to 5°C. The reaction time is 10 minutes to 4 hours, preferably 10 minutes to 1 hour.

Step b: Then, the compound obtained in step a is isolated or as it is! In the presence of a base, 1.0 to 2.0 molar equivalents of the compound of formula
Stirring is carried out at ~100°C, preferably -25~50°C to obtain the 3-thio substituted product of formula (1). The reaction time varies depending on the type of base used, the type of compound of formula (1), and the reaction temperature, but is 10 minutes to 5 hours, and usually 10 minutes to 2 hours.

Suitable organic solvents in Step a and Step S include N
, N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, tesetonitrile, tetrahydrofuran, dichloromethane, etc., and these can be used alone or in combination. Preferred bases include organic bases such as diisopropylethylamine, N,N-dimethylaminopyridine, N,N-dimethylaniline, and triethylamine; It is 1.5 molar equivalent.

Step C: Next, 7 of the compound of formula (1) obtained in the above step
The protecting group at the amino group is removed by methods commonly used in the field of beta-lactam chemistry to provide compounds of formula V. For example, when the protecting group R5 of the compound 2) is a phenoxyacetyl group, phenylacetyl group, or benzoyl group, the formula
Dissolve the compound in dichloromethane or benzene, add 1.5 to 2.0 molar equivalents of phosphorus pentachloride and 2.0 to 3.0 molar equivalents of pyridine.
Add 0 molar equivalents and incubate at -40 to 30 °C for 30 minutes to 3
Stir for an hour.

Next, add a large excess of methanol at -50 to 20°C, stir for 30 minutes to 2 hours, add a large excess of water, and -
Stir at 50-20° C. for 30 minutes to 1 hour to obtain the compound of formula V.

In addition, when the protecting group R' of the compound of formula (2) is a trityl group, the compound of formula (1) is dissolved in a solvent that does not participate in the reaction (for example, ethyl acetate), and under water cooling, p-toluenesulfonic acid and
By adding 1.0 to 1.5 molar equivalents of monohydrate and stirring for 1 to 5 hours, compound (7) para-toluenesulfonate of formula V can be obtained. This para-toluenesulfonate salt can be treated with a base to form the free compound of formula V, if necessary.

Step d: To obtain a compound of formula (1) from a compound of formula V, the compound of formula V is reacted with a 2-aminothiazole acetic acid derivative of formula (1) in the presence of a condensing agent, or the compound of formula V is reacted with a 2-aminothiazoleacetic acid derivative of formula (1). react a reactive derivative of the compound. Here, the condensing agent includes N,N'-dicyclohexylcarbodiimidonyl-2-ethoxy-1,2-dihydroquinoline, carbonyldiimidazole, diphenylphosphoric acid azide, Vilsmeier's reagent, and the like. In addition, reactive derivatives of the compound of formula (II) include acid halides (e.g.
(acid bromides), acid anhydrides (e.g. symmetrical acid anhydrides of compounds of formula ■ or mixed acid anhydrides with ethyl chlorocarbonate, diphenyl phosphoric acid, methanesulfonic acid, etc.), activated esters (e.g. paranitrophenol, thiophenol) ,
esters with N-hydroxysuccinimide, etc.).

Taking as an example a mixed acid anhydride of the compound of formula (■) with methanesulfonic acid as a reactive derivative of the compound of formula (■),
First, the compound of formula (■) is dissolved in a solvent that does not participate in the reaction, and -
In the presence of a base at 70 to -30°C, add 1.0 to 1.1 molar equivalents of methanesulfonic acid chloride and stir for 20 to 40 minutes to prepare a mixed acid anhydride of the compound of formula (1). To this, in the presence of a base, 0.5 to 0.7 molar equivalents of the compound of formula V are added within the range of -70 to -30°C, and the mixture is stirred for 20 to 40 minutes to obtain a compound of formula (1).

Preferred solvents in this step include N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane, and chloroform.

Also suitable bases are diisopropylethylamine, triethylamine, N. N-dimethylaniline, N. N-
Dimethylaminopyridine, pyridine, etc. are used in an amount of 1.0 to 2.2 molar equivalents based on the compound of formula V.

When using an acid chloride as a reactive derivative of the compound of formula (1), first dissolve the compound of formula (1) in a solvent that does not participate in the reaction, and add 1 phosphorus pentachloride in the presence of a base at -30 to -10°C. Add .0 to 1.1 molar equivalents and stir for 10 to 30 minutes to prepare the acid chloride of the compound of formula (1). To this, a solution of 0.7 to 1.0 molar equivalents of the compound of formula V dissolved in a solvent not involved in the same reaction as above was added within the range of -30 to 0 °C, and the mixture was stirred for 10 to 30 minutes. Obtain the compound ■. Preferred solvents in this step are dichloromethane,
Chloroform, acetonitrile, N. N-dimethylformamide, etc. Also suitable bases are pyridine,
Triethylamine, N. N-dimethylaminopyridine,
N. N-dimethylaniline, diisopropylethylamine, etc., and the amount used is 4.0% for the compound of formula V.
~5.5 molar equivalents.

Step C: To obtain the compound of formula (2) from the compound of formula (1), the protecting group of the compound of formula (1) is removed by methods such as hydrolysis and reduction that are frequently used in the field of β-lactam chemistry.

(1) Hydrolysis Hydrolysis is usually preferably carried out in the presence of an acid, and examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, and methanesulfone. Examples include organic acids such as acid, benzenesulfonic acid, and para-toluenesulfonic acid. Furthermore, instead of the above acids, Lewis acids such as boron trifluoride, boron trifluoride etherate, aluminum trichloride, antimony pentachloride, ferric chloride, tin chloride, titanium tetrachloride, zinc chloride, and acidic ion exchangers can be used. Resin or the like may also be used.

Further, when using the above-mentioned organic acid or Lewis acid, it is desirable to carry out the reaction in the presence of a cation scavenger such as anisole. Preferred solvents for hydrolysis are, for example, water, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, dioxane, dichloromethane, nitromethane and the like. Moreover, when the above-mentioned acid is a liquid, it can also be used as a solvent itself.

(2) Reduction Reduction is performed by chemical reduction or catalytic reduction method. Examples of reducing agents used in chemical reduction include combinations of metals such as zinc and iron and organic acids such as formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, and hydrobromic acid, or ammonium chloride.

Examples of the catalyst used in the catalytic reduction include platinum black 1, platinum oxide, palladium black, palladium carbon, and Raney nickel.

The reduction is usually carried out in a conventional solvent that does not adversely affect the reaction, such as water, methanol, ethanol, acetic acid, tetrahydrofuran, N,N-dimethylformamide, or dioxane.
or in a mixture thereof.

Although the reaction temperature for the above-mentioned hydrolysis and reduction is not particularly limited, it is usually carried out under cooling or heating.

The compound of formula I of the present invention and its non-toxic salts not only exhibit strong antibacterial activity against various pathogenic bacteria including Gram-positive bacteria and Durham-negative bacteria, but also exhibit excellent oral absorbability and Useful as an antibacterial agent for administration.

For this purpose, the compounds of the invention can be administered orally in dosage forms such as tablets, sachets, capsules, and granules prepared according to conventional formulation techniques. In each of the above formulations, conventional fillers, binders, disintegrants,
Additives such as H regulators and solubilizers can be used.

The dose of the compound of the present invention to be administered to a patient may vary depending on the patient's age, type of disease, condition, etc., but usually 10 to 3000 mg can be administered in one to several doses per day.

Next, the results of antibacterial activity and oral absorption tests of the compounds of the present invention are shown.

Test Example 1 Antibacterial tests against various bacteria were conducted using the agar plate dilution method (inoculated amount: 10' cells/mQ), and the results shown in Table 1 below were obtained.

Table 1 [MIC value (w, /mfl)] (Note) A: Compound obtained in Example 1(e) (sodium salt)
shows.

B: Indicates cephalexin (known compound).

C: Indicates cefixime (sodium salt, known compound).

D-nia β-(2-(2-aminothiazol-4-yl)
-2-[(Z)-carboxymethoxyimino]acetamide)-3-[(Z)-2-methoxycarbonylvinylthio]-3-cephem-4-carboxylic acid (known compound).

Test Example 2 Changes in blood concentration over time were investigated by oral administration to male Wistar rats (7 weeks old, 3 rats per group).

Drug dosage: 50 mg/kg (5% gum arabic suspension) Assay method: Bioassay method (test bacteria: Escherichia coli 5C507) The results are shown in Table 2.

(Note) A: Compound (sodium salt) obtained in Example 1 (e)
shows.

B: Indicates cephalexin (known compound).

Examples Next, the method for producing the compounds of the present invention will be explained in more detail in Examples.

Example 1 (a) 34.3 g (64, smM) of 7β-phenylacetamide-3-methanesulfonyloxy-3-cephem-4-carboxylic acid paramethoxybenzyl ester was added to N,N
-Dissolved in 100ml of dimethylformamide at -30°C
70% sodium bisulfide 5.68g (71.0mM)
A solution of 50ml of N,N-dimethylformamide and 12.5g (96.9mM) of diisopropylethylamine were added and stirred for 30 minutes.

After the reaction, 500 mQ of water was added and the mixture was washed with 300 ml of ethyl acetate. The aqueous layer was adjusted to pH 2-3 with 0.5% hydrochloric acid, extracted with 11 ethyl acetate, and extracted with saturated brine (300 ml
3) and then dried with anhydrous magnesium sulfate. The solvent was distilled off, and n-hexane was added to the residue, which was then powdered to obtain 22.0 g of 7β-phenylacetamide-3-mercapto-3-cephem-4-carboxylic acid paramethoxybenzyl ester.

NMR(CDC4)3) 8 (ppm);3.
32 (LH, d, J = 18Hz> 3.46 (IH, d, J = 18Hz> 3.62 (2H, s) 3.78 (3H, s) 4, 98 (IH, d, J = 5Hz) 5.18 (28, s) 5.35 (LH, s) 5, 63 (IH, dd, J=5Hz, 9Hz) 6,
42 (IH, d, J=9Hz) 6.88 (28, d, J=8Hz) 7, 20-7.40 (7H, m> KBr-1゜IRν max ell + 3250.1760.1650.1510, 1350,
1230.1170(b) 7β-phenylacetamide-3-mercapto-3-cephem-4 obtained in (a) above
-Carboxylic acid paramethoxybenzyl ester 22.0g
(46.8mM) in N,N-dimethylformamide 15
0rnfL and added 5.89g (70.1mM) of propiolic acid methyl ester and 1.81g (14.0mM) of diisopropylethylamine at -20°C.
After stirring for 0 minutes, 300 ml of 0.5% hydrochloric acid was added, extracted with 700 ml of ethyl acetate, and saturated brine (300 ml) was added.
ml x 3) and dried over anhydrous magnesium sulfate. The solvent was distilled off, diethyl ether was added to the residue, and it was powdered to give 7β-phenylacetamide-3-[(Z)-2
-Methoxyluponylvinylthioko-3-cephem-4
-Carboxylic acid paramethoxybenzyl ester 16.2g
I got it.

NMR(CDC4)3)δ(ppm);3,44
(LH, d, J = 18H2) 3, 64 (2H, s) 3, 74 (IH, d, J = 18Hz) 3, 76 (3H, s) 3, 79 (3H, s) 4, 98 (IH , d, J: 5) 1 z) 5.21 (2H, s) 5, 84 (IH, dd, J = 5 Hz, 9 Hz) 5, 90
(IH, d, cloHz) 6.31 (IH, d, J=9Hz> 6.86 (2H, d, J=8Hz) 6.95 (IH, d, J=10Hz) 7.24-7. 44 (7H, m) KBr −1.

IRν max"' 3250.1780.1690.1510.1355.
1220.1165(c) 7β-phenylacetamide
18.3 g (33° OmM) of 3-[(Z)-2-methoxycarbonylvinylthioko 3-cephem-4-carboxylic acid paramethoxybenzyl ester was dissolved in 200 ml of anhydrous dichloromethane and cooled to 0°C. To this, 7.82 g (99.0 mM) of pyridine and 13.0 g of phosphorus pentachloride.
After adding 7 g (65.8 mM) and raising the reaction temperature to room temperature over 30 minutes, the mixture was further stirred at the same temperature for 1 hour. Then, the reaction solution was cooled to -50°C, 100ml of anhydrous methanol was added, and the mixture was stirred at -20°C for 1 hour.

Subsequently, the reaction solution was cooled to -50°C and added with 100ml of water.
was added and stirred for 40 minutes under water cooling.

Add saturated sodium bicarbonate solution to this to make it weakly basic, extract with 300 td of ethyl acetate, and add 200 ml of saturated brine! After washing with water, it was dried with anhydrous magnesium sulfate. The solvent was distilled off, diethyl ether was added to the residue, and the mixture was powdered to obtain 10.6 g of 7β-amino-3-[(Z)-2-methoxycarbo, nylvinylthio]-3-cephem-4-carboxylic acid paramethoxybenzyl ester. I got it.

NMR(CD(J)3)δ(ppm); 1.7
1 (2H, s) 3, 48 (IH, d, J = 18Hz> 3, 78 (3H, s) 3, 80 (IH, d, J = 18Hz) 3.81 (3) 1.s) 4, 79 (1B, d, J: 5Hz) 4, 99 (IH
, d, J=5Hz>5,25(28,s) 5,90(lH,d,J=tooZ>6,87(2H,d,J=8Hz>6,97(lH,d,J=1ouZ >7,34(2H,d,J=8Hz>KBr-1.

IRν m, x Cm' 3320.1755.1705.1690.1610.
1510.

1345.1220.1165 (d) 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2,4-dimethoxybenzyloxyimino]acetic acid 531 mg (0.92 mM>N,N- Dissolved in 10ml of dimethylformamide, added 124mg (0.96mM) of diisopropylethylamine,
Cooled to 0°C. To this, methanesulfonic acid chloride 10
5 mg (0.92 mM) was added and stirred for 30 minutes. Then 7β-amino-3-[(Z)-2-methoxycarbonylvinylthio E-s-cephem-4-carboxylic acid paramethoxybenzyl ester 200a+g (0,46
mM> and diisopropylethylamine 60 mg (0,4
6mM) was added at the same temperature and stirred for 30 minutes. After the reaction,
Add 30 ml of water, extract with 50 td of ethyl acetate, and 30 ml of saturated brine! After washing with water, it was dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate:benzene-1:4) to give 7β-(2-(2-)cutylaminothiazol-4-yl)-2-[ (Z)-2,4-dimethoxybenzyloxyiminocoacetamide) -3-[
(Z)-2-methoxycarbonylvinylthio]-3-
270 mg of cephem-4-carboxylic acid paramethoxybenzyl ester was obtained.

NMR(CD(J)a)δ(ppm);3,1
2 (LH, d, J = 17Hz) 3, 60 (18, d, J = 17Hz) 3, 70 (38, s) 3, 75 (3H, 9) 3.77 (3H, s) 3, 80 ( 3H, s) 3, 94 (LH, d, J = 5Hz) 5, 22 (2B, s) 5, 23 (LH, d, J = 10Hz) 5, 34 (IH, d, J = 10Hz) 5. 81 (IH, dd, J=5Hz, 9Hz) 5, 94
(1B, d, J=10Hz) 6, 35-6.47 (2H, m) 6.83 (1) 1. s) 6.86 (2H, d, J = 8Hz> 6, 93 (IH, d, J: 10Hz) 6, 98 (IH
, bs) 7, 20-7.40 (19H, m) KBr-1.

IRν maxcffl' 3380.1790, 1700, 1615.1590.
1515.

1480.1360.1290.1220.1160.
1115.1035(e) Trifluoroacetic acid 3.5m
7β-(
2-(2-tritylaminothiazol-4-yl)-2
250 mg (0,25 mM > was added and stirred for 40 minutes, and further stirred for 10 minutes at room temperature.
After the reaction, the reaction solution was mixed with ether and n-hexane (1:2.
The precipitated crystals were collected by filtration and 7β-(2-(2-aminothiazol-4-yl)-2-[(Z)-hydroxyiminocoacetamide)-
3-[(Z)-2-methoxycarbonylvinylthio]-
Trifluoroacetate of 3-cephem-4-carboxylic acid 1
Next, these crystals and 43 mg (Q, 51 mM) of sodium bicarbonate were dissolved in 4 ml of water, and then subjected to Sephadex LH-20 column chromatography (elution solvent: water) to obtain 7β-(2-( Sodium salt of 2-aminothiazol-4-yl)-2-[(Z)-hydroxyimino]acetamide)-3-[(Z)-2-methoxycarbonylvinylthioko-3-cefeyun-4-carboxylic acid 120 mg I got it.

NMR(D!O) 8 (pI)nt) ;3,5
7 (IH, d, J = 17Hz>3, 77 (3H, s) 3, 97 (IH, d, J = 17) 1z) 5, 32 (1
8, d, J=5Hz) 5,89 (LH, d, J=5Hz) 6,04 (IH, d, , Cl0Hz) 7.00 (18
, s) 7, 32 (IH, d, J=10H2) KBr −1.

IRν ll, ax ” ' 3260.1765, 1675.1610, 1525,
1390°1355.1230.1200.1175.
1135 120 mg of the sodium salt obtained above was added to 5 ml of water.
The pH was adjusted to 2.5 by adding 10% hydrochloric acid under water cooling, and the precipitated crystals were collected by filtration to give 7β-(2-(2-aminothiazol-4-yl)-2-[(Z) 80 mg of -hydroxyimino]acetamide) -3-[(Z)-2-methoxycarbonylvinylthio]-3-cephem-4-carboxylic acid was obtained.

NMR(DMSO-da)S(pl)Ill)
;3,66(3H,s) 3,67(IH,d,J=17Hz) 4,06(IH,d,J:17Hz) 5,20(IH,dJ=5Hz) 5,83(IH,dd , J=5Hz, 8Hz>6.0
3 (IH, d, J = 10H2) 6.67 (IH, s) 7.14 (2H, bs) 7, 51 (11, d, J = 10Hz) 9, 52 (IH, d, J = 8Hz) Br −1 at 11.33 (IH, s).

IRν max Cm' 3345, 1775, 1675, 1630, 1
435, 1390.

1360.1230.1175.1005 Example 1 (b
), according to the procedure and reaction conditions disclosed in Section 3 below.
The compounds illustrated in the table were obtained.

In each table below, G is a phenylacetamide group, DMB is a 2,4-dimethoxybenzyl group, and T
r is a trityl group, PMB is a paramethoxybenzyl group, Bh is a benzhydryl group, and POM is a pivaloyloxymethyl group.

Table 3 (Continued) Based on the operation and reaction conditions disclosed in Example 1(C), the corresponding compounds were selected from the compounds obtained in Examples 2(b) to 4(b) in Table 3. The compounds exemplified in Table 4 below were obtained.

Table 4 (Continued) Based on the operation and reaction conditions disclosed in Example 1(d), the corresponding compounds were prepared from the compounds obtained in Examples 2(C) to 4(C>) in Table 4. The compounds exemplified in Table 5 below were obtained.

Based on the operation and reaction conditions disclosed in Example 1(e), from the compounds obtained in Examples 2(d) to 4(d) in Table 5, the corresponding compounds in Table 6 below were prepared. The exemplified compounds were obtained.

Table 6 (continued)

Claims (1)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents a hydrogen atom or a protecting group for an amino group, R^2 represents a hydrogen atom or a protecting group for a hydroxyl group, and R^3
represents a hydrogen atom or a protecting group for a carboxyl group, and R^4
represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. ) Cephalosporin derivatives and non-toxic salts thereof.